title: FHOD1, a formin upregulated in epithelial-mesenchymal transition, participates in cancer cell migration and invasion.
abstract: Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Gardberg
authors.forename: Katja
authors.initials: K
authors.lastname: Kaipio
authors.forename: Laura
authors.initials: L
authors.lastname: Lehtinen
authors.forename: Piia
authors.initials: P
authors.lastname: Mikkonen
authors.forename: Vanina D
authors.initials: VD
authors.lastname: Heuser
authors.forename: Kati
authors.initials: K
authors.lastname: Talvinen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Caroline
authors.initials: C
authors.lastname: Kampf
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlen
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.forename: Mari
authors.initials: M
authors.lastname: Koivisto
authors.forename: Olli
authors.initials: O
authors.lastname: Carpén
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D048430:Cell Shape; D004727:Endothelium / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D000080865:Formins; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D018307:Neoplasms, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D005326:Fetal Proteins; D000080865:Formins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; C120021:FHOD1 protein, human